This invention relates to a method of stimulating post-trauma immune response in warm-blooded animals including humans. More particularly, this invention relates to a method of regulating cytokine activity in vivo, moderating cytokine excesses in response to injury, and potentiating cellular response to enhance resistance to infection by administering exogenous melatonin.
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone produced in and secreted by the pineal gland of humans and other warm-blooded animals. The highest levels of secreted melatonin occur during the dark period of a circadian light-dark cycle. This hormone is also found in the retina and the gut.
Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, control of circadian rhythms, and modulation of retinal physiology. Retinal melatonin has been implicated in photoreceptor outer disc shedding and phagocytosis, in melanosome aggregation in pigment epithelium, and cone photoreceptor retinomotor movement. Of the various physiological processes that have been associated with melatonin, those best substantiated are its effects on sexual maturation, ovarian function, and chronobiological rhythms. J. Arendt, 8 Oxford Review of Reproductive Biology 266-320 (1986); M. Dubocovich, Pharmacology and Function of Melatonin Receptors, 2 FASEB J. 2765 (1988).
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats. Cassone et al., 1 J. Biol. Rhythms 219 (1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms. J. Arendt et al., 292 Br. Med. J. 1170 (1986).
Alterations in immune response following traumatic injury, including dysregulation of immune cell cytokine secretion, are a result of a dynamic neuroendocrine process reflecting the attempted adaptive response of an injured host. The most widely investigated component of this process of adaptation to a stressful challenge is the hypothalamic-pituitary-adrenal (HPA) axis, the activation of which results in the well known elevation of glucocorticoid levels in trauma patients. V. Vaughan et al., Cortisol and Corticotropin in Burned Patients, 22 J. Trauma 263 (1982). There is considerable evidence for the suppressive effects of glucocorticoid on immune function, which may play a role in trauma-associated immune suppression. T. Cupps & A. Fauci, Corticosteroid-Mediated Immunoregulation in Man, 65 Immunol. Rev. 134 (1982).
Recent work has revealed that other neural products associated with the stress response also have immune regulating activity, suggesting that both the nervous and immune systems use these signal molecules in adaptive responses. A. Dunn, Recent Advances in Psychoneuroimmunology, 3 Curr. Opinions in Psychiatry 103 (1990); R. Dantzer & K. Kelley, Stress and Immunity: An Integrated View of Relationships between the Brain and Immune System, 44 Life Sciences 1995 (1989); T. Roszman & S. Carlson, Neurotransmitters and Molecular Signaling in the Immune Response, in Psychoneuroimmunology 311-35 (R. Ader, D. Felten, N. Cohen eds., 2d ed., 1991). Neuropeptides influence immune reactivity by direct and indirect pathways, including tissue distribution, proliferative and synthetic responses, and cytotoxic activities of lymphocytes. Evidence for direct effects on immune response is strengthened by the discovery that immune cells possess receptors for these neural derived molecules. D. Carr & J. Blalock, Neuropeptide Hormones and Receptors common to the Immune and Neuroendocrine Systems: Bidirectional Pathway of Intersystem Communication, in Psychoneuroimmunology 573-88 (R. Ader, D. Felten, N. Cohen eds., 2d ed., 1991). These neural/immune system interactions may occur in a hormonal (via circulation), paracrine (released from nerves), or autocrine (produced by immune cells themselves) fashion.
Nerve mapping studies have revealed innervation of lymphoid organs, including the thymus, spleen, lymph nodes, and bone marrow, with evidence for secretion of neurotransmitters in the immediate lymphoid microenvironment. S. Felten a D. Felten, Innervation of Lymphoid Tissue, in Psychoneuroimmunology 27-61 (R. Ader, D. Felten, N. Cohen eds., 2d ed., 1991). Additionally, there is evidence that T cells produce ACTH, .beta.-endorphin, and corticotropin-releasing hormone molecules that are identical to the neural product, thereby setting the stage for paracrine and autocrine delivery to immune cells of these regulatory molecules. E. Goetzl et al., Production and Recognition of Neuropeptides by Cells of the Immune System, in Psychoneuroimmunology 263-82 (R. Ader, D. Felten, N. Cohen eds., 2d ed., 1991); H. Besedovsky & A. Del Ray, Physiological Implications of the Immune-Neuro-Endocrine Network, in Psychoneuroimmunology 589-608 (R. Ader, D. Felten, N. Cohen eds., 2d ed., 1991).
Discoveries in neuroimmunologic research have also revealed that immune cell cytokine secretion is under neuroendocrine control. M. Caroleo et al., Melatonin as Immunomodulator in Immunodeficient Mice, 23 Immunopharmacology 81 (1992); V. Gobbo et al., Pinealectomy Inhibits Interleukin-2 Production and Natural Killer Cell Activity in Mice, 11 Int. N.J. Immunopharmacology 567 (1989); No Spector a E. Korneva, Neurophysiology, Immunophysiology and Neuroimmunomodulation, in Psychoneuroimmunology 449-73 (R. Ader, D. Felten, N. Cohen eds., 2d ed., 1991). However, understanding of the mechanisms responsible for central nervous system (CNS) regulation of immune response and cytokine production is incomplete, and very little in known about the role of this process in regulation of host immune response following trauma.
Melatonin appears to have immunostimulatory effects in models of stress. M. Caroleo et al., Melatonin as Immunomodulator in Immunodeficient Mice, 23 Immunopharmacology 81 (1992); V. Gobbo et al., Pinealectomy Inhibits Interleukin-2 Production and Natural Killer Cell Activity in Mice, 11 Int. N. J. Immunopharmacology 567 (1989); G. Maestroni et al., Pineal Melatonin, Its Fundamental Immunoregulatory Role in Aging and Cancer, 521 Ann. N.Y. Acad. Sci. 140 (1988). Recently it has been observed that disruption of light/dark cycles induces significant changes in the CNS, with subsequent alterations in several physiologic functions, including immune response. B. Radosevic-Stasic et al., Immune Response of Rats after Pharmacologic Pinealectomy, 5 Period Biol. 282 (1983); R. Wurtman & f. Waldhauser, Melatonin in Humans, J. Neural Transmission Supp. 21 (1986). Mediation of these changes appears to be linked to the pineal gland and melatonin. G. Maestroni et al., Role of the Pineal Gland in Immunity: Circadian Synthesis and Release of Melatonin Modulates the Antibody Response and Antagonizes the Immunosuppressive Effect of Corticosterone, 13 J. Neuroimmunol. 19 (1986); G. Maestroni & A. Conti, Role of the Pineal Neurohormone Melatonin in the Psycho-Neuroendocrine-Immune Network, in Psychoneuroimmunology 495-513 (R. Ader, D. Felten, N. Cohen eds., 2d ed., 1991). Melatonin is known to act at the hypothalamic level, W. Pierpaoli & Y. Changxian, The Involvement of Pineal Gland and Melatonin in Immunity and Aging. I. Thymus-Mediated, Immunoreconstituting, and Antiviral Activity of Thyrotropin-Releasing Hormone, 27 J. Neuroimmunol. 99 (1990), affecting thermoregulation and pituitary release of certain hormones, W. Pierpaoli & Y. Changxian, 27 J. Neuroimmunol. 99 (1990); J. Beck-Friis et al., The Pineal Gland in Affective Disorders, in The Pineal Gland: Endocrine Aspects 313-25 (G. Brown, S. Wainwright eds., 1985). The pineal gland and melatonin have been reported to exert an oncostatic effect on carcinogenesis and tumor growth, W. Regelson a W. Pierpaoli, Melatonin: A Rediscovered Antitumor Hormone? Its Relation to Surface Receptors, Sex Steroid Metabolism, Immunologic Response, and Chronobiologic Factors in Tumor Growth and Therapy, 5 Cancer Invest. 379 (1985), and neoplastic diseases have been associated with immune depression and altered plasma melatonin levels, P. Lissoni et al., Endocrine Effects of a 24 Hour Intravenous Infusion of Interleukin-2 in the Immunotherapy of Cancer, 10 Anticancer Res. 753 (1990); P. Lissoni et al., Endocrine and Immune Effects of Melatonin Therapy in Metastatic Cancer Patients, 25 Eur. J. Cancer. Clin. Oncol. 789 (1989); P. Lissoni et al., Alterations of Pineal Gland and of T Lymphocyte Subsets in Metastatic Cancer Patients: Preliminary Results, 3 J. Biol. Regulators and Homeostatic Agents 181 (1990). Administration of exogenous melatonin has been shown to enhance several immune parameters in normal and restraint-stressed mice. G. Maestroni et al., Pineal Melatonin, Its Fundamental Immunoregulatory Role in Aging and Cancer, 521 Ann. N.Y. Acad. Sci. 140 (1988). There have also been reports of melatonin-mediated up-regulation of T cell interleukin-2 (IL-2) production in mice that were immunodeficient because of extremes of age or cyclophosphamide therapy. M. Caroleo et al., Melatonin as Immunomodulator in Immunodeficient Mice, 23 Immunopharmacology 81 (1992). Similarly, pinealectomy was shown to inhibit IL-2 production and natural killer cell (NK) activity in mice, while administration of exogenous melatonin in pinealectomized mice restored IL-2 production and NK activity. V. Gobbo et al., Pinealectomy Inhibits Interleukin-2 Production and Natural Killer Cell Activity in Mice, 11 Int. N.J. Immunopharmacology 567 (1989). Thus, melatonin appears to exert immunoenhancing effects in several models of immunodeficiency. Additionally, peak plasma melatonin levels have been shown to be significantly depressed in burn patients, G. Vaughn et al., Pineal Function in Burns: Melatonin Is Not a Marker for General Sympathetic Activity, 2 J. Pineal Res. 1 (1985). Cytokine secretion alterations have been noted following injury, including decreases in IL-2, N. Moss et al., Temporal Correlation of Impaired Immune Response after Thermal Injury with Susceptibility to Infection in a Murine Model, 104 Surgery 882 (1988). The possible role for melatonin in immune function alterations following thermal injury has not been previously evaluated. Further, there is no evidence linking in vivo administration of exogenous melatonin to regulation of cytokines IL-6 and .delta.-IFN.